The use of chemotherapeutics of treat cancer is well established. Examples of chemotherapeutics finding established application in the treatment of cancers include by way of examples tamoxifen, toremifene, cisplatin, methotrexate, adriamycin, to name but a few. Often such chemotherapeutics are utilized in combination, i.e., as coctails in chemotherapeutic regimens, and often in combination with other types of therapies, e.g., radiation, surgery or antibody-based therapeutics.
While chemotherapeutics have had success in treating a number of different types of cancers, e.g., some leukemia, breast cancer and prostate cancer, chemotherapy is fraught with problems. For example, chemotherapeutics exhibit toxicity to non-targeted tissue, e.g., they may cause nephrotoxicity. Another prevalent problem with chemotherapy is that tumor tissues may become resistant to a particular chemotherapeutic. For example, it is known that some tumors become resistant to cisplatin.
In order to alleviate such problems, it is known to administer chemotherapeutics in combination thereby minimizing the risk that the tumor will become resistant to the chemotherapeutic regimen. However, this solution is less than satisfactory, as it does not eliminate the fact that some tumors should become resistant to chemotherapy. This is disadvantageous as it produces the efficiency of such chemotherapeutic, e.g., requiring that they be administered in greater dosages to elicit cytotoxicity. This is problematic as the risk of systemic toxicity to non-targeted tissues increases. Also, it may significantly increase the cost of treatment.
It is similarly known that tumors may become resistant to ionizing radiation. For example, it has been reported that tumor resistance may be correlated with the expression of certain oncogenes such as ras, raf, cot, mos and myc as well as growth factors such as PDGF and FGF, among others.
The use of oligonucleotides for treatment of cancer has also been reported, in particular antisense oligonucleotides that target oncogenes or other genes expressed by the particular cancer. However, antisense therapy is also subject to some problems that inhibit efficacy, particularly the fact that such oligonucleotides can be unstable in vivo and, therefore, may become degraded before they reach the target site, e.g., tumor cell or viral infected cell.
Attempts to increase the potency of oliogs have included the synthesis of several analogs, with modifications directed primarily to the phosphodiester backbone. For example, phosphorothioate oligonucleotides have demonstrated enhanced resistance to nuclease digestion. Other modifications to oligonucleotides have included derivatization with lipophilic moieties such as cholesterol, and polylysine to enhance cellular uptake. Alternatively, the polyanionic nature of the molecule has been eliminated in methylphosphonate analogs.
Another reported approach has involved the use of cationic liposomes to enhance delivery. Bennet et al., Mol. Pharmacol., 4:1023–1033 (1992). Zelphati et al., J. Lipsome Res., 7(1):31–49 (1997); Thierry et al., Biochem. Biophys. Res. Comm., 190(3):952–960 (1993). It is widely accepted that cationic liposomes must contain enough charge to neutralize the negatively charged oligonucleotides as well as providing enough residual positive charge to the complex to facilitate interaction with a negatively charged cell surface. (Litzinger et al., J. Liposome Research, 7(1): 51–61 (1997)). However, problems associated with previous cationic liposomal delivery systems similarly include serum-instability, undesirable biodistribution, and target-non-specificity, which hinder their use for efficient nucleic acid delivery in vivo.
Therefore, methods for improving treatment of chemoresistant tumors would be highly beneficial.